Dataset Information

The CFTR gene variants in Japanese children with idiopathic pancreatitis.

ABSTRACT: The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of CFTR have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey CFTR variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of PRSS1 and SPINK1. The entire CFTR gene was sequenced in the patients by combining LA-PCR and next-generation sequencing analysis. To determine a splice-affecting variant, CFTR expression was investigated in the nasal epithelial cells by RT-PCR. One (3.6%) and 15 (53.6%) of 28 patients had pathogenic and functionally affected variants in the CFTR gene, respectively. Two variants, p.Arg352Gln and p.Arg1453Trp, were found more frequently in the patients compared with one in Japanese healthy controls (p?=?0.0078 and 0.044, respectively). We confirmed skipping of exon 10 in the nasal epithelial cells in one patient having a splice-affecting variant (c.1210-12?T(5)) in intron 9. Functionally affected variants of the CFTR gene are not so rare in Japanese paediatric patients with idiopathic pancreatitis. Surveying CFTR gene variants in a Japanese sample could help identify pancreatitis risk in these children.

SUBMITTER: Iso M

PROVIDER: S-EPMC6459923 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The CFTR gene variants in Japanese children with idiopathic pancreatitis.

Iso Manami M Suzuki Mitsuyoshi M Yanagi Kumiko K Minowa Kei K Sakurai Yumiko Y Nakano Satoshi S Satou Kazuhito K Shimizu Toshiaki T Kaname Tadashi T

Human genome variation 20190411

The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of CFTR have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey CFTR variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of P ...[more]

PMID: 30992994

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Project description:The aim of the study was to define the spectrum of genetic risk factors of chronic pancreatitis (CP) development in patients living in the European part of the Russian Federation.Materials and methodsThe study group included 105 patients with CP, with the age of the disease onset under 40 years old (the average age of onset was 26.9 years). The control group consisted of 76 persons without clinical signs of pancreatitis. The diagnosis of chronic pancreatitis in patients was made on the basis of clinical manifestations and the results of laboratory and instrumental investigations. Genetic examination of patients was conducted using the next-generation sequencing (NGS) technology and included targeted sequencing of all exons and exon-intron boundaries of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes. The genotyping of the rs61734659 locus of the PRSS2 gene was also conducted.ResultsGenetic risk factors of the CP development were found in 61% of patients. Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). The frequent gene variants in Russian patients with CP were as follows: CTRC gene - c.180C>T (rs497078), c.760C>T (rs121909293), c.738_761del24 (rs746224507); cumulative odds ratio (OR) for all risk alleles was 1.848 (95% CI: 1.054-3.243); CFTR gene - c.3485G>T (rs1800120), c.1521_1523delCTT (p.Phe508del, rs113993960), and c.650A>G (rs121909046); OR=2.432 (95% CI: 1.066-5.553). In the SPINK1, PRSS1, and CPA1 genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the SPINK1 gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the PRSS1 gene - c.86A>T (p.Asn29Ile, rs111033566); of the CPA1 gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) CTRC according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the CTRC gene, the variant c.493+49G>C (rs6679763) appeared to be benign, the c.493+51C>A (rs10803384) variant was frequently detected among both the diseased and healthy persons and did not demonstrate a protective effect. The protective factor c.571G>A (p.Gly191Arg, rs61734659) of the PRSS2 gene was detected only in the group of healthy individuals and confirmed its protective role. 12.4% of the patients with CP had risk factors in 2 or 3 genes.ConclusionSequencing of the coding regions of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes allowed to identify genetic risk factors of the CP development in 61% of cases. Determining the genetic cause of CP helps to predict the disease course, perform preventive measures in the proband's relatives, and facilitate a personalized treatment of the patient in future.

Project description:CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.

Dataset Information

The CFTR gene variants in Japanese children with idiopathic pancreatitis.

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The <i>CFTR</i> gene variants in Japanese children with idiopathic pancreatitis.

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